4tpt: Difference between revisions

Revision as of 10:48, 15 March 2023

Crystal Structure of the Human LIMK2 Kinase Domain In Complex With a Non-ATP Competitive Inhibitor

Structural highlights

4tpt is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Ligands:	35H
Resources:	FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Function

LIMK2_HUMAN Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro.^[1] ^[2]

Publication Abstract from PubMed

The first allosteric, type III inhibitor of LIM-kinase 2 (LIMK2) is reported. A series of molecules that feature both an N-phenylsulfonamide and tertiary amide were not only very potent at LIMK2 but also were extremely selective against a panel of other kinases. Enzymatic kinetic studies showed these molecules to be noncompetitive with ATP, suggesting allosteric inhibition. X-ray crystallography confirmed that these sulfonamides are a rare example of a type III kinase inhibitor that binds away from the highly conserved hinge region and instead resides in the hydrophobic pocket formed in the DFG-out conformation of the kinase, thus accounting for the high level of selectivity observed.

Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation.,Goodwin NC, Cianchetta G, Burgoon HA, Healy J, Mabon R, Strobel ED, Allen J, Wang S, Hamman BD, Rawlins DB ACS Med Chem Lett. 2014 Aug 7;6(1):53-7. doi: 10.1021/ml500242y. eCollection 2015, Jan 8. PMID:25589930^[3]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

References

↑ Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999 Aug 6;285(5429):895-8. PMID:10436159
↑ Sumi T, Matsumoto K, Nakamura T. Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase. J Biol Chem. 2001 Jan 5;276(1):670-6. PMID:11018042 doi:10.1074/jbc.M007074200
↑ Goodwin NC, Cianchetta G, Burgoon HA, Healy J, Mabon R, Strobel ED, Allen J, Wang S, Hamman BD, Rawlins DB. Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation. ACS Med Chem Lett. 2014 Aug 7;6(1):53-7. doi: 10.1021/ml500242y. eCollection 2015, Jan 8. PMID:25589930 doi:https://dx.doi.org/10.1021/ml500242y

Proteopedia Page Contributors and Editors (what is this?)

OCA

[1] Maekawa M, Ishizaki T, Boku S, Watanabe N, Fujita A, Iwamatsu A, Obinata T, Ohashi K, Mizuno K, Narumiya S. Signaling from Rho to the actin cytoskeleton through protein kinases ROCK and LIM-kinase. Science. 1999 Aug 6;285(5429):895-8. PMID:10436159

[2] Sumi T, Matsumoto K, Nakamura T. Specific activation of LIM kinase 2 via phosphorylation of threonine 505 by ROCK, a Rho-dependent protein kinase. J Biol Chem. 2001 Jan 5;276(1):670-6. PMID:11018042 doi:10.1074/jbc.M007074200

[3] Goodwin NC, Cianchetta G, Burgoon HA, Healy J, Mabon R, Strobel ED, Allen J, Wang S, Hamman BD, Rawlins DB. Discovery of a Type III Inhibitor of LIM Kinase 2 That Binds in a DFG-Out Conformation. ACS Med Chem Lett. 2014 Aug 7;6(1):53-7. doi: 10.1021/ml500242y. eCollection 2015, Jan 8. PMID:25589930 doi:https://dx.doi.org/10.1021/ml500242y

[1]

[2]

[3]

@@ Line 3: / Line 3: @@
 <StructureSection load='4tpt' size='340' side='right'caption='[[4tpt]], [[Resolution|resolution]] 2.60&Aring;' scene=''>
 == Structural highlights ==
-<table><tr><td colspan='2'>[[4tpt]] is a 2 chain structure with sequence from [http://en.wikipedia.org/wiki/Human Human]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TPT OCA]. For a <b>guided tour on the structure components</b> use [http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4TPT FirstGlance]. <br>
+<table><tr><td colspan='2'>[[4tpt]] is a 2 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=4TPT OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=4TPT FirstGlance]. <br>
-</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat"><scene name='pdbligand=35H:N-{4-[(1S)-1,2-DIHYDROXYETHYL]BENZYL}-N-METHYL-4-(PHENYLSULFAMOYL)BENZAMIDE'>35H</scene></td></tr>
+</td></tr><tr id='ligand'><td class="sblockLbl"><b>[[Ligand|Ligands:]]</b></td><td class="sblockDat" id="ligandDat"><scene name='pdbligand=35H:N-{4-[(1S)-1,2-DIHYDROXYETHYL]BENZYL}-N-METHYL-4-(PHENYLSULFAMOYL)BENZAMIDE'>35H</scene></td></tr>
-<tr id='gene'><td class="sblockLbl"><b>[[Gene|Gene:]]</b></td><td class="sblockDat">LIMK2 ([http://www.ncbi.nlm.nih.gov/Taxonomy/Browser/wwwtax.cgi?mode=Info&srchmode=5&id=9606 HUMAN])</td></tr>
+<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=4tpt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tpt OCA], [https://pdbe.org/4tpt PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=4tpt RCSB], [https://www.ebi.ac.uk/pdbsum/4tpt PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=4tpt ProSAT]</span></td></tr>
-<tr id='activity'><td class="sblockLbl"><b>Activity:</b></td><td class="sblockDat"><span class='plainlinks'>[http://en.wikipedia.org/wiki/Non-specific_serine/threonine_protein_kinase Non-specific serine/threonine protein kinase], with EC number [http://www.brenda-enzymes.info/php/result_flat.php4?ecno=2.7.11.1 2.7.11.1] </span></td></tr>
-<tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[http://oca.weizmann.ac.il/oca-docs/fgij/fg.htm?mol=4tpt FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=4tpt OCA], [http://pdbe.org/4tpt PDBe], [http://www.rcsb.org/pdb/explore.do?structureId=4tpt RCSB], [http://www.ebi.ac.uk/pdbsum/4tpt PDBsum], [http://prosat.h-its.org/prosat/prosatexe?pdbcode=4tpt ProSAT]</span></td></tr>
 </table>
 == Function ==
-[[http://www.uniprot.org/uniprot/LIMK2_HUMAN LIMK2_HUMAN]] Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro.<ref>PMID:10436159</ref> <ref>PMID:11018042</ref>
+[https://www.uniprot.org/uniprot/LIMK2_HUMAN LIMK2_HUMAN] Displays serine/threonine-specific phosphorylation of myelin basic protein and histone (MBP) in vitro.<ref>PMID:10436159</ref> <ref>PMID:11018042</ref>
 <div style="background-color:#fffaf0;">
 == Publication Abstract from PubMed ==
@@ Line 24: / Line 22: @@
 __TOC__
 </StructureSection>
-[[Category: Human]]
+[[Category: Homo sapiens]]
 [[Category: Large Structures]]
-[[Category: Non-specific serine/threonine protein kinase]]
+[[Category: Burgoon HA]]
-[[Category: Burgoon, H A]]
+[[Category: Cianchetta G]]
-[[Category: Cianchetta, G]]
+[[Category: Goodwin NC]]
-[[Category: Goodwin, N C]]
+[[Category: Hamman BL]]
-[[Category: Hamman, B L]]
+[[Category: Healy J]]
-[[Category: Healy, J]]
+[[Category: Mabon S]]
-[[Category: Mabon, S]]
+[[Category: Rawlins DB]]
-[[Category: Rawlins, D B]]
+[[Category: Strobel ED]]
-[[Category: Strobel, E D]]
+[[Category: Wang S]]
-[[Category: Wang, S]]
-[[Category: Dfg inhibitor]]
-[[Category: Limk2 kinase]]
-[[Category: Transferase-transferase inhibitor complex]]

4tpt: Difference between revisions

Revision as of 10:48, 15 March 2023

Crystal Structure of the Human LIMK2 Kinase Domain In Complex With a Non-ATP Competitive Inhibitor

Structural highlights

Function

Publication Abstract from PubMed

References

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Proteopedia Page Contributors and Editors (what is this?)

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